This invention is generally in the field of microneedles useful in medical applications, and more particularly to coated microneedles for drug delivery and sensing, such as transdermally.
Biopharmaceuticals, such as peptides, proteins, and future uses of DNA and RNA, represent a rapidly growing segment of pharmaceutical therapies (Walsh, Trends Biotechnol 23:553-58 (2005)). These drugs are delivered almost exclusively by the parenteral route, as the oral route is generally unavailable due to poor absorption, drug degradation, and low bioavailability. However, conventional parenteral administration with hypodermic needles undesirably requires expertise for delivery, can lead to accidental needle sticks, and causes pain, which results in reduced patient compliance. Given these problems, efforts have been made to develop alternate drug delivery routes to replace hypodermic needles (Orive et al., Curr Opin Biotechnol 14:659-64 (2003)). It would be desirable to provide drug delivery methods and devices that avoid the limitations and disadvantages associated with the use of conventional hypodermic needles.
Transdermal drug delivery is an especially attractive alternative to conventional hypodermic needles, because it is usually easy to use, safe, and painless (Prausnitz et al., Nat Rev Drug Discov 3:115-24 (2004)). The tough barrier posed by the skin's outer layer of stratum corneum has limited the applicability of this method to drugs that are hydrophobic, low molecular weight, and potent, as the stratum corneum's barrier properties severely limit passive delivery of most drugs, especially macromolecules and microparticles.
The use of micron-scale needles assembled on a transdermal patch has been proposed as a hybrid between hypodermic needles and transdermal patches that can overcome the problems of both injections and patches (Prausnitz et al., Microneedles In Percutaneous Penetration Enhancers (Smithand & Maibach, eds), pp. 239-55, CRC Press, Boca Raton, Fla., 2005)). Microneedles have been shown to be painless in human subjects relative to hypodermic needles (Mikszta et al., Nat. Med. 8:415-19 (2002); Kaushik et al., Anesth Analg 92:502-04 (2001). Unlike transdermal patches, microneedles also have been successfully used to deliver a variety of compounds into the skin, including macromolecules. In vitro skin permeability enhancement of two to four orders of magnitude has been observed for small molecules (e.g., calcein) and large compounds (e.g., proteins and nanoparticles) (Henry et al., J Pharm Sci 87:922-25 (1998); McAllister, et al., Proc Natl Acad Sci USA 100:13755-60 (2003)). In vivo delivery has been shown for peptides, such as insulin and desmopressin (Martanto et al., Pharm. Res. 21:947-52 (2004); Cormier, et al., J Control Release 97:503-11 (2004)); genetic material, including plasmid DNA and oligonucleotides (Lin et al., Pharm. Res. 18:1789-93 (2001); Chabri et al., Br J Dermatol 150:869-77 (2004)); and vaccines directed against hepatitis B and anthrax (Mikszta et al., Nat. Med. 8:415-19 (2002); Mikszta et al., J Infect Dis 191:278-88 (2005)).
Four different modes of microneedle-based drug delivery have been primarily investigated (Prausnitz, Adv Drug Deliv Rev 56:581-87 (2004); Prausnitz et al., Microneedles In Percutaneous Penetration Enhancers (Smithand & Maibach, eds), pp. 239-55, CRC Press, Boca Raton, Fla., 2005). These modes are (1) piercing an array of solid microneedles into the skin followed by application of a drug patch at the treated site (Henry, J. Pharm. Sci. 87:922-25 (1998)); (2) coating drug onto microneedles and inserting them into the skin for subsequent dissolution of the coated drug within the skin (Cormier et al., J Control Release 97:503-11 (2004)); (3) encapsulating drug within biodegradable, polymeric microneedles followed by insertion into skin for controlled drug release (J-H Park, et al., Pharma. Res. 23:1008-19 (2006)); and (4) injecting drug through hollow microneedles (Zahn et al., Biomed Microdevices 2:295-303 (2000)).
Among these approaches, coated microneedles are attractive for rapid bolus delivery of high molecular weight molecules into the skin, which can be implemented as a simple ‘Band-Aid’-like system for self-administration. Furthermore, storing a drug in a solid phase coating on microneedles may enhance long-term stability of the drug, even at room temperature. For instance, desmopressin coated onto microneedles has been shown to maintain 98% integrity after six months storage under nitrogen at room temperature (Cormier et al., J Control Release 97:503-11 (2004)). Coated microneedles are also particularly attractive for vaccine delivery to the skin, because antigens can be targeted to epidermal Langerhans cells and dermal dendritic cells for a more potent immune response. For example, a strong immune response against a model ovalbumin antigen delivered from coated microneedles has been shown in guinea pigs (Matriano et al., Pharm Res 19:63-70 (2002)).
While the microneedle itself can be fabricated by adapting the tools of the microelectronics industry for inexpensive, mass production (Reed & Lye, Proc IEEE 92:56-75 (2004)), precise coating of microneedles presents technical challenges. Among the various conventional coating processes, such as dip coating, roll coating and spray coating (Bierwagen, Electrochim. 37:1471-78 (1992)), dip coating is particularly appealing for coating microneedles because of its apparent simplicity and ability to coat complex shapes. A conventional dip-coating process typically involves submerging and withdrawing an object from a coating solution, and then drying the continuous liquid film adhering to the surface of the object to yield a solid coating. However, such dip coating to coat microneedles by simply dipping and withdrawing them from an aqueous solution of a compound (e.g., calcein, sulforhodamine or vitamin B) results in non-uniform coatings with frequent spreading of the solution to the substrate from which the microneedles extend. Moreover, predictions of dip-coating theory to produce uniform coatings from different coating solutions mostly apply to static equilibrium systems; dynamic systems as in the case of dip coating are more complex. In addition, because surface tension-driven phenomena often take place on the micron scale, conventional dip-coating methods have difficulty coating specified sections of micron-dimensioned structures, especially when those structures are closely spaced. For instance, bridging of liquid coating material between closely spaced microneedles is problematic. It therefore would be desirable to provide a micron-scale, dip coating process to coat microneedles with uniform and spatially controlled coatings using methods suitable for a breadth of drugs and biopharmaceuticals.
U.S. Pat. No. 6,855,372 to Trautman et al. discloses processes and apparatus for coating skin-piercing microprojections, in which dipping is done by moving the microprojections tangentially across and through a thin film of liquid on a rotating drum. Usefulness of the process would appear to be limited due to the tendency of ripple formation in the film while dipping microprojections. Ripples would cause liquid to touch and coat the substrate that carries the microprojections or would cause differences in coating length of microprojections on the leading and trailing edge of the array. The method also would appear be restricted to certain dip lengths and to certain microprojection spacings, given that wicking of liquid up between closely spaced microprojections and onto the base of the device would still be expected to be a problem. It therefore would be desirable to provide microneedle coating processes that reduces or eliminates between-needle wicking and offers better coating uniformity and better control of dip/coating length on each microneedle. It would also be desirable to provide improved methods for precisely coating microneedles or other microstructures with a variety of materials, including materials other than homogeneous liquid solutions.